Field of the Invention
The present disclosure generally relates to methods of treating and preventing posttraumatic stress disorder (PTSD) in humans. More particularly, the present disclosure is directed to a method of treating and preventing PTSD, and the like by administration of intranasal insulin to the upper one-third of a patient's nasal cavity.
Description of the Related Art
Posttraumatic stress disorder (PTSD) is a severe anxiety central nervous system disorder that may develop in response to exposure to an event resulting in psychological trauma. PTSD may be less frequent and more enduring than the more commonly seen posttraumatic stress. PTSD is believed to be triggered by a subject witnessing or experiencing any of a wide range of events that produce intense negative feelings of fear, helplessness, or horror. This experienced fear may trigger many split-second changes in the body to prepare to defend against or avoid the danger. The “fight-or-flight” response is a healthy reaction meant to protect a person from harm. But it is believed that with PTSD, this reaction is altered. People suffering from PTSD may feel stressed or frightened even when they are not in danger. PTSD symptoms may include reliving the traumatic event in the form of flashbacks, or nightmares, for example. Further, symptoms of PTSD may include avoidance of places or things that are reminders of the experience; feeling emotionally numb; feeling anxious; and/or losing interest in formerly enjoyable activities. People suffering from PTSD may also experience hyperarousal symptoms such as being easily startled; feeling tense; and having difficulty sleeping for example.
If these symptoms are experienced for no more than a few weeks, the disorder may be referred to as acute stress disorder, or ASD. If the symptoms last more than a few weeks and become an ongoing problem, they might be diagnosed as PTSD. Some people with PTSD have few or no symptoms for weeks or even months following the event.
The main treatments for people with PTSD include psychotherapy, medications, or both. Sertraline (Zoloft®) and paroxetine (Paxil®), both of which are antidepressants, have been approved by the FDA for treating people with PTSD and are administered systemically, typically orally. The most common side effects of antidepressants like sertraline and paroxetine, also administered systemically, include: headache, nausea, agitation, sexual problems, and/or sleeplessness or drowsiness. Other types of systemically-administered medications may also be prescribed for people suffering from PTSD, such as benzodiazepines, antipsychotics, or other antidepressants. There is little information on how well these medications work for people with PTSD.
Further, the known medications are not necessarily targeting the physiological areas of the brain directly affected by PTSD and the known medications have side effects. The primary reason for this is that known medications are administered systemically, generally orally. Since the biological conditions leading to PTSD occur within the CNS and require treatment within the CNS, only a small percentage of each, e.g., orally, systemically administered dose of the medications discussed above will actually reach the CNS. This is due to several factors, some of which include: the medication in the patient's bloodstream goes through metabolic changes, some of the medication will be removed by the liver and other organs and/or be highly susceptible to protein binding, and the medication must also then cross the blood-brain barrier (BBB), which excludes most medium to large molecules. Accordingly, an excessively large dose of the medication must be administered systemically in order to achieve the therapeutic dose or concentration within the patient's CNS. This excessive dosing is undesirable as the patient's system, including organs and tissues are exposed to the medication and may be adversely affected, even dangerously affected.
Accordingly, a need exists for a therapeutic agent(s) or compound(s) that may be used to treat and/or prevent PTSD and other like disorders, which can be administered with a therapeutic dose, i.e., an effective amount of the therapeutic agent(s), that is delivered directly and targeted to the CNS for the treatment of PTSD and/or to help protect the brain from damage due to traumatic psychological stress which helps prevent PTSD while minimizing systemic exposure to the therapeutic agent or compound. Further, a need exists for such a therapeutic agent or compound that minimizes the adverse side effects generally associated with administration of drugs used to treat PTSD. Still further, a need exists for a delivery system for such a composition that provides for enhanced uptake of the composition to maximize the therapeutic effect obtained per administration.
Further, it is known that intranasal administration of therapeutic compounds or agents may, in some cases, increase the effectiveness of certain therapeutic compounds or agents in bypassing the blood brain barrier (BBB) and delivering the compound or agent directly to the CNS. Thus, intranasal administration of therapeutic compounds may allow increased prevention and/or treatment of certain diseases or conditions.
It is also known that greater than 98% of small molecule and nearly 100% of large molecule CNS drugs developed by the pharmaceutical industry do not cross the BBB. Intracerebroventricular or intraparenchymal drug administration can directly deliver therapeutics to the brain; however, these methods are invasive, inconvenient, and impractical for the numbers of individuals requiring therapeutic interventions for treating CNS disorders. Intranasal drug administration to the upper one-third of the patient's nasal cavity is a non-invasive and convenient means to rapidly target therapeutics of varying physical and chemical properties to the CNS. The olfactory and trigeminal neural pathways connecting the nasal passages to the CNS are clearly involved in the delivery of therapeutic compounds applied via intranasal administration to the upper third of the nasal cavity. In addition to these neural pathways, perivascular pathways, and pathways involving the cerebrospinal fluid or nasal lymphatics may play a central role in the distribution of therapeutics from the nasal cavity to the CNS.
The general intranasal method of drug delivery, i.e., administration to the lower two-thirds of the patient's nasal cavity, holds great promise as an alternative to more invasive routes, however, a number of factors limit the efficiency of general intranasal delivery to the CNS. Absorption of intranasally applied drugs into the capillary network in the nasal mucosa can decrease the amount of drug available for direct transport into the CNS. Additional factors within the nasal cavity, including the presence of nasal mucociliary clearance mechanisms, metabolizing enzymes, efflux transporters and nasal congestion can also reduce the efficiency of delivery into the CNS. In particular, therapeutic compounds may be absorbed into the blood and/or delivered to peripheral (non-target) tissues, thus reducing delivery of the compound to the target. As a result, the efficacy of administering therapeutic compounds to the lower two-thirds of the nasal cavity with the goal of delivering therapeutics to the CNS is greatly diminished. Further, the efficacy of administering therapeutic compounds to the upper one-third of the nasal cavity as a means to target therapeutics to the CNS could also be improved.
The method of administration of insulin to the upper one-third of the nasal cavity for treatment of neurodegenerative disorders, specifically Alzheimer's disease, provides the basis for the present invention. Insulin has been shown to improve memory in healthy adults, with no change in blood levels of insulin or glucose. See, e.g., Benedict C., et al (2004), Intranasal insulin improves memory in humans, Psychoneuroendocrinology, 29:1326-1334; Craft (2012), Alzheimer disease: Insulin resistance and AD—Extending the translational path. Nat Rev Neurol. 8:360-362; Reger et al., (2006), Effects of intranasal insulin on cognition in memory in memory-impaired older adults: Modulation by APOE genotype. Neurobiol Aging. 27:451-458; Reger, et al., (2008), Intranasal insulin improves cognition and modulates beta-amyloid in early AD, Neurology. 70-440-448.
Insulin is an effective treatment of Alzheimer's disease because glucose uptake and use are significantly decreased in patients with Alzheimer's disease. See de Leon, et al., (1997), Cortisol reduces hippocampal glucose metabolism in normal elderly, but not in Alzheimer's disease. J Clin Endocrinol Metab., 82:3251-3269. Glucose is the only source of energy used by brain cells under normal conditions, and the brain cells of patients with Alzheimer's disease are starved for energy. Alzheimer's disease has been reported to involve a deficiency of insulin and insulin signaling in the brain.
However, insulin is far more than simply a treatment agent for Alzheimer's symptoms. When insulin reaches the brain, it stimulates the formation of insulin-degrading enzyme, which is capable of degrading beta amyloid, one of the principal abnormal proteins known to accumulate in the brains of patients with Alzheimer's disease. Further, the activity of glycogen-synthase kinase-3-beta, the enzyme that phosphorylates tau to create Alzheimer's disease neurofibrillary tangles, has been reported to be downregulated in response to insulin. Finally, insulin receptor signaling increase synaptic density, and loss of synapses is key to the neuropathology of Alzheimer's disease.
Alzheimer's disease and PTSD have several relevant things in common. First, both disorders are characterized by elevations in blood levels of cortisol which can increase beta amyloid and tau pathology in rodent models of Alzheimer's disease. In patients with Alzheimer's disease, increased plasma cortisol levels are associated with more rapid disease progression. Second, the hippocampus, an area key to memory and emotional response, is damaged by elevated cortisol that inhibits the uptake of glucose needed by brain cells for energy. Hippocampal degeneration is common in Alzheimer's disease and has also been reported in patients with PTSD. Third, FDG-PET imaging reveals decreased uptake and utilization of glucose in both patients with AD (Li et al., 2008) and those with PTSD, although results with PTSD appear to be more variable. Finally, deficits in verbal declarative memory have been reported in patients with PTSD and short-term memory deficits are characteristic of patients with Alzheimer's disease.
Stress has been found to reduce the uptake and use of glucose by brain cells. See Sapolsky (1986), Glucocorticoid toxicity in the hippocampus: Reversal by supplementation with brain fuels. J Neurosci. 6:2240-2244. Multiple mechanisms are likely involved in this action, one of which is the inhibition of glucose use in the hippocampus by glucocorticoids. Cortisol has been reported to reduce hippocampal glucose use in healthy elderly adults on the basis of examination of the brain glucose use response to hydrocortisone. It is likely that glucocorticoids also reduce the capacity of the hippocampus to survive neurological insults because glucocorticoids inhibit glucose transport 15% to 30% in both primary and secondary hippocampal astrocytic cultures; this could impair the ability of astrocytes to aid neurons by removing damaging glutamate from the synapse during times of neurological crisis. Virgin, et al, (1991), Glucocorticoids inhibit glucose transport and glutamate uptake in hippocampal astrocytes: Implications for glucocorticoid neurotoxicity, J Neurochem. 57:1422-1428.
Mean cerebrospinal (CSF) cortisol concentrations are significantly higher in combat veterans with PTSD than in healthy comparison subjects. Baker et al, (2005), Higher levels of basal serial CSF cortisol in combat veterans with posttraumatic stress disorder, Am J Psychiatry. 5:992-994. Thus, cortisol levels are higher in individuals diagnosed with PTSD.
Further, in a study assessing the cortisol response to a cognitive challenge, patients with PTSD had 61% higher group mean cortisol levels in the time leading up to the cognitive challenge. Thus, cortisol levels are higher for individuals anticipating a stressing challenge. In this same study, the PTSD patients had cortisol levels 46% higher than the controls. Bremner et al, (2003), Cortisol response to a cognitive stress challenge in posttraumatic stress disorder (PTSD) related to childhood abuse. Psychoneuroendocrinology 28:733-750. And, recently, glucocorticoids have been shown to induce PTSD-like memory impairments in mice. Kaouane N (2012) Glucocorticoids can induce PTSD-like memory impairments in mice. Science, 335:1510-1513.
It would be desirable to provide a method of preventing and/or treating PTSD by directly delivering an effective amount of PTSD to the target within the patient's CNS. It would also be desirable to reduce absorption of intranasally-administered therapeutic compounds or agents, in this case insulin, for prevention and treatment of PTSD, into the blood and delivery to non-target or peripheral tissues. It would be further desirable to increase deposition and delivery of the therapeutic compounds or agents to, inter alia, the CNS, e.g., within the olfactory epithelium, the olfactory bulbs as well as the lymphatic system, and it would be desirable to increase therapeutic compound targeting relative to the blood to the frontal cortex, anterior olfactory nucleus, hippocampus, hypothalamus, pons, midbrain, medulla, cerebellum and to the meninges. It would be further desirable to provide an intranasal delivery method and pharmaceutical composition(s) that are effective and efficient in facilitating delivery, and maximum efficiency of delivery, of therapeutic compounds, e.g., insulin, to the CNS.
The present invention addresses, inter alia, these issues.